A Phase I/II trial of MK-3475 (pembrolizumab) in children’s solid tumors and lymphoma

• Register: EUCTR
• Last refreshed on: 17 November 2014
• Main ID: EUCTR2014-002950-38-Outside-EU/EEA
• Date of registration: 10/11/2014
• Prospective Registration: Yes
• Primary sponsor: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
• Public title: A Phase I/II trial of MK-3475 (pembrolizumab) in children’s solid tumors and lymphoma
• Scientific title: A Phase I/II Study of Pembrolizumab (MK-3475) in Children with advanced melanoma or a PD-L1 positive advanced, relapsed or refractory solid tumor or lymphoma (KEYNOTE-051) - A Phase I/II trial of MK-3475 (pembrolizumab) in children’s solid tumors and lymphoma
• Target sample size: 311
• Recruitment status: NA
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-002950-38
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: no Randomised: no Open: no Single blind: no Double blind: no Parallel group: no Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: no Other: no Number of treatment arms in the trial: 6

Countries of recruitment

France, United Kingdom, United States

Contacts

• Name: Global Clinical Trials Operations
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck

• Name: Global Clinical Trials Operations
• Affiliation: Merck Sharp & Dohme Corp., a subsidiary of Merck

Key inclusion & exclusion criteria

Inclusion criteria:
1. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be between 6 months and less than 18 years of age on day of signing informed consent/assent.
3. Have histologically or cytologically-documented, locally-advanced, or metastatic solid malignancy that is incurable and has either (a) failed prior standard therapy, (b) for which no standard therapy exists, or (c) standard therapy is not considered appropriate by the patient and treating physician. There is no limit to the number of prior treatment regimens.
4. Be able to provide tissue from an archival tissue sample or newly obtained core or excisional biopsy of a tumor lesion not previously irradiated (tumors progressing in a prior site of radiation are allowed for characterization, other exceptions may be considered after Sponsor consultation).
5. Have either advanced melanoma or a PD-L1 positive advanced, relapsed or refractory solid tumor or lymphoma as determined by IHC in archival formal fixed paraffin embedded tumor (FFPET) or newly obtained biopsy. (Subjects with PD-L1 negative tumors may be enolled in Part II of the trial in selet tumor types where preliminary response is observed)
6. Have measurable disease based on RECIST 1.1. Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. During Part I of the trial, subjects with neuroblastoma may be enrolled with evaluable disease.
7. Have a performance status as defined below:
• Lansky Play Scale =70 for children up to and including 16 years of age;
• Karnofsky score =70 for children > 16 years of age
8. Demonstrate adequate organ function
9.Female subject of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.
10. Female subjects of childbearing potential should be willing to use 2 methods of birth control or be surgically sterile, or abstain from heterosexual activity for the course of the study through 120 days after the last dose of study medication.
11. Male subjects should agree to use an adequate method of contraception starting with the first dose of study therapy through 120 days after the last dose of study therapy.

Are the trial subjects under 18? yes
Number of subjects for this age range: 311
F.1.2 Adults (18-64 years) no
F.1.2.1 Number of subjects for this age range
F.1.3 Elderly (>=65 years) no
F.1.3.1 Number of subjects for this age range

Exclusion criteria:
1. Is currently participating and receiving study therapy in,or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment.
3. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to mAbs administered more than 4 weeks earlier.
4. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., = Grade 1 or at baseline) from adverse events due to a previously administered agent.
5. Has a known additional malignancy that is progressing or requires active treatment with limited exceptions.
6. Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging [using the same imaging techniques for diagnosis and follow-up] for at least four weeks prior to the first dose of trial treatment and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability. Patients with primary CNS tumors or metastases of primary CNS tumors are not excluded but must be neurologically stable (e.g. without a progression of neurologic symptoms or requiring systemic steroid therapy within last 2 weeks).
7. Has an active autoimmune disease that has required systemic treatment in past 2 years
8. Has evidence of interstitial lung disease.
9. Has an active infection requiring systemic therapy.
10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
11. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 120 days after the last dose of trial treatment.
13. Has received prior therapy with an anti-PD-1, anti-PD-L1, and anti-PD-L2 (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways). Subjects with melanoma who previously received treatment with ipilimumab are not excluded.
14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).
16. Has received a live vaccine within 30 days of planned start of study therapy.
17. Is or has an immediate family member (e.g., spouse, parent/legal guardian, sibling or child) who is investigational site or sponsor staff directly involved wi

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Treatment of advanced melanoma or advanced, relapsed or refractory PD-L1 positive malignant solid tumor or lymphoma in children from 6 months to less than 18 years old.

Therapeutic area: Diseases [C] - Cancer [C04]

Intervention(s)

Product Name: Pembrolizumab
Product Code: MK-3475 (SCH 900475)
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: PEMBROLIZUMAB
CAS Number: 1374853-91-4
Current Sponsor code: MK-3475
Other descriptive name: Anti-PD-1 monoclonal antibody
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 25-

Primary Outcome(s)

Primary end point(s): The primary safety endpoints are AEs graded using CTCAE (Version 4.0) criteria. Safety will be assessed by quantifying the toxicities and grades experienced by subjects who have received pembrolizumab, including serious adverse events (SAEs) and events of clinical interest (ECIs).

The primary efficacy endpoint is overall response rate, defined as the proportion of subjects in the analysis population who have complete response (CR) or partial response (PR) using RECIST 1.1 at any time during the study. Response for the primary analysis will be determined by the investigator assessment, and a confirmation assessment is required per RECIST 1.1.

Timepoint(s) of evaluation of this end point: Safety Endpoints: Dose limiting toxicities will be evaluated in the first cycle of treatment (Q3W dosing) or the first two cycles of treatment (Q2W dosing). Safety endpoints will be evaluated for all treated subjects from initiation of treatment through the protocol defined safety follow-up period of 90 days for SAEs (unless a given subject initiates new anti-cancer therapy, in which case the follow-up period for that subject is 30 days)
Efficacy Endpoints: Efficacy will be evaluated every 8 weeks after initiation of trial treatment until disease progression.

Secondary Objective: (1) Objective: To characterize the pharmacodynamics (i.e., stimulation of IL-2 response) of pembrolizumab when administered as monotherapy to children pooled across all indications
(2) Objective: To evaluate clinical activity of pembrolizumab within each tumor type as measured by:
• ORR by irRECIST
• Duration of response by RECIST 1.1
• Duration of response by irRECIST
• Disease control rate by RECIST 1.1
• Disease control rate by irRECIST
• Progression free survival by RECIST 1.1
• Progression free survival by irRECIST
• Overall survival
(3) Objective: To evaluate the relationship between baseline tumor PD-L1 expression and clinical efficacy outcomes.
(4) Objective: To evaluate the relationship between predictive markers of response and clinical efficacy outcomes.

Main Objective: (1) Objective: To define the rate of dose-limiting toxicities (DLTs) at the maximum tolerated dose (MTD) or maximum administered dose (MAD) of pembrolizumab when administered as monotherapy to children from 6 months to < 18 years of age pooled across all indications including advanced melanoma or a PD-L1 positive advanced, relapsed or refractory solid tumor or lymphoma.
(2) Objective: To characterize the pharmacokinetics (PK) of pembrolizumab when administered as monotherapy to children from 6 months to < 18 years of age pooled across all indications
(3) Objective: To determine the safety and tolerability of pembrolizumab based on AEs, and clinical and laboratory measures in children from 6 months to <18 years of age pooled across all indications
(4) Objective: To evaluate anti-tumor activity of pembrolizumab in children from 6 months to <18 years of age within each tumor type based on RECIST 1.1.

Secondary Outcome(s)

Secondary end point(s): Secondary efficacy endpoints include: (1) duration of response, defined as time from first RECIST 1.1 response to disease progression in subjects who achieve a PR or better; (2) progression-free survival (PFS), defined as the time from allocation to the first documented disease progression according to RECIST 1.1 or death due to any cause, whichever occurs first; (3) disease control rate, defined as the proportion of subjects with best overall response of complete responses (CR), partial responses (PR), or stable disease (SD), and (4) overall survival (OS).
Additional supportive analyses of overall response rate, duration of response, and PFS will be conducted using a modified RECIST 1.1 criteria (irRECIST), in which a confirmation assessment of disease progression must be obtained at least 4 weeks after the initial disease assessment indicating progressive disease.

Timepoint(s) of evaluation of this end point: Efficacy will be evaluated every 8 weeks after initiation of trial treatment until disease progression.

Secondary ID(s)

3475-051

051

Source(s) of Monetary Support

Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.